Background: CNS mets, a common complication of melanoma, are associated with poor survival prognosis (median of 4-5 months). The rationale for combining PD-L1 pathway blockade using atezolizumab (A) with the small molecule BRAF pathway–targeted inhibitors cobimetinib (C) and vemurafenib (V) for the treatment of BRAF^V600 mutation–positive melanoma is based on preclinical and translational evidence supporting the synergistic antitumoral effects of these approaches. Recently, the phase 3 IMspire150 study (NCT02908672) demonstrated improved progression-free survival outcomes with A + C + V vs C + V. Methods: This phase 2 study (NCT03625141) is currently evaluating A + C + V in pts with BRAF^V600 mutation–positive advanced melanoma and CNS mets. The study originally included a parallel cohort evaluating A + C in pts with BRAF^V600wild-type advanced melanoma and CNS mets. This cohort was closed at an enrollment of 15 pts after the primary analysis of the phase 3 IMspire170 study (NCT03273153), which showed no added benefit with A + C vs pembrolizumab in pts with BRAF^V600 wild-type disease. Eligible pts are aged ≥18 years with histologically confirmed melanoma and magnetic resonance imaging–confirmed brain mets ≥5 mm in at least 1 dimension. In addition, pts should not have received prior systemic treatment for metastatic disease; they were required to have ECOG performance status ≤2 and adequate hematologic and end organ function. Prior stereotactic or surgical therapy of ≤10 brain mets is allowed. The primary endpoint is intracranial objective response rate (ORR) with A + C + V in BRAF^V600mutation–positive melanoma as assessed by an independent review committee. Key secondary endpoints include investigator-assessed intracranial ORR, extracranial ORR, overall ORR, safety, and quality of life. Exploratory biomarker analyses are planned. The sample size for the cohort will be approximately 60 pts. No formal statistical hypothesis is being tested in this study. The primary study analysis and the analyses of all efficacy endpoints and safety summaries will be based on data collected ≤6 months after the last pt is enrolled. Clinical trial information: NCT03625141